Fig. 4: Patient neurons show action potential exhaustion driven by reduced sodium currents.

a First two dimensions (44% variance explained) of a principal component analysis of 21 measured features from patient (n = 132 (Pt1 n = 77, Pt2 n = 55)) and control (n = 94 (Ct1 n = 59, Ct2 n = 35)) neurons. Greyscale represents 3 identified neuronal types, type 1 (light grey, T1, n = 60), type 2 (dark grey, T2, n = 64), and type 3 (black, T3, n = 102). b Current-clamp, representative traces from T1, T2, or T3 neurons in response to depolarizing current injection. c Proportional generation of classified neurons of control (Ct1, Ct2) and patient (Pt1, Pt2). d Correlation matrix of 21 features in patient (bottom-left, orange) and control (top-right, blue) neurons. Positive correlations indicated by red and negative by blue. Features with significance P = < 0.01 are displayed on the matrix, values above are blank. e Top, overlayed traces from T3 control and patient neurons. Bottom, attenuation ratio from 102 measured T3 neurons. f Phase plots of 2 overlayed single action potentials from representative T3 control and patient neurons. g Depolarisation (left, maximum dV/dt) and repolarisation (right, minimum dV/dt) velocities. h Voltage-clamp, representative overlay of currents evoked by step to −30 or −20 mV in control and patient neurons, respectively. Inset is an enlarged section of the initial segment. i Peak control (n = 67) and patient (n = 66) sodium current densities. j Peak and steady control (n = 67) and patient (n = 66) potassium current densities. In (i–j), current densities are normalised to capacitance, and variation is SD and present as shaded area. In e and g, datapoints represent one neuron, data are pooled into control (2 independent lines) and patient (2 independent lines), significance is by t-test and reported with p-value adjustment using Holm, and whiskers represent 1.5·IQR.